The treatment of cancer via the re-activation of the immune system is a long-standing goal of medical research. There have been many attempts to stimulate an immune response to cancer including the application of therapeutic vaccines (Umansky et al.), the use of immune stimulants such as Toll-Like Receptor Agonists (TLRa) (Fahey et al.), the use of autologous cell vaccination in combination with immune stimulators including TLRa and Annexin V (US2006293226), the use of therapeutic acute infections and the use of expression constructs containing cancer antigens in a virus like vehicle (Pascolo).
Although effective in certain patients these strategies have not provided general means to treat cancer. One of the many reasons for this is that cancers are by definition immune evasive given that their very detection is a result of their having successfully avoided normal immune responses. One of the evasion strategies of cancers is the production of an immune suppressive environment around the tumour through the secretion of various signals and cytokines notably TGFbeta. Other authors have noted that Nuclear Factor kappa B (NF-kB) is a critical mediator of ongenic processes, although it is not itself mutated in cancer (Karin) and probably plays a role via underlying inflammation in permitting tumour expansion.
It is now apparent that tumour macrophage are an important component of this immune suppression process. Hagemann et al. (1988), noted that macrophage that support tumour expansion were IL-10 high, IL-12 low, scavenger receptor expression high, and TNF-α high. Genetic inhibition of NF-kB activation by ablation of inhibitor of kappa kinase B (IKKB) resulted in a reversion of this phenotype and a reduction in tumour growth.
NF-kB is well known to interact with p38 kinase in stimulated cells, and inhibitors of p38 kinase can modulate the degree to which NF-kB dependant gene products are produced (Ulive et al.). p38 kinase has been widely investigated for a potential role in cancer therapy because of its general importance in cell cycle control, proliferation and differentiation (Bradham and McClay).
With this knowledge, many workers have attempted to modulate cancer using p38 kinase inhibitors. However, many such studies have been done with prototypic, non-selective p38 inhibitors and data, where positive, have tended to show modest improvements in therapy (see Han et al., 2009). In certain instances, improvements in therapy are reliant on the p38-MAPK pathway to induce apoptosis (Kadowaki et al., 2009) and where it is inhibited by a non-selective p38 kinase inhibitor, there is a reduction of anti-tumour effect (see Liu et al., 2009). In certain instances it has been demonstrated that the resistance of certain tumours to the effects of a therapeutic antibody are mediated by the MAP kinase pathway. In such a setting the addition of a MAP kinase inhibitor, in this case BIRB 796, increased cytotoxic effect of bortezomib (Yasui et al., 2007).
Indeed almost all p38 MAP kinase inhibitors are tested for lack of cytotoxicity using cell-lines which are often of tumour derived. It is, therefore, not surprising that p38 MAP kinase inhibitors are not known widely as anti-cancer agents or for direct anti-tumor activity.
Less appreciated is the fact that p38 and related kinase inhibitors have specific temporal and spatial effects that are dependant on the cell environment in which they act. The environment of a tumour is specific, and the signaling in the cells in that environment is different to that say, in the peritoneum of a normal animal exposed to bacterial antigens. Thus, recognition of the value of kinase inhibitors for the promotion of anti-tumour immune responses is reliant on evaluating them in that context. An example of this is provided by Wang et al., 2006 who show that dendritic cells rely on p38 to respond to certain tumour signals emanating from multiple myeloma like cell lines.